Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.80+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017525036 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43124016-C-T is Pathogenic according to our data. Variant chr17-43124016-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124016-C-T is described in Lovd as [Pathogenic]. Variant chr17-43124016-C-T is described in Lovd as [Pathogenic].
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
- -
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Dec 27, 2023
This sequence change affects a donor splice site in intron 2 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 22034289). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 55710). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 30, 2019
Variant summary: BRCA1 c.80+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence, confirming in a minigene splicing assay that this variant affects mRNA splicing, causing exon 2 skipping (Steffensen_2014). The variant was absent in 251038 control chromosomes (gnomAD). c.80+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Fackenthal_2012, Rebbeck_2018 and disease-specific databases). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Mar 03, 2020
This variant causes a G to A nucleotide substitution at the +1 position of intron 2 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A minigene assay has shown that this variant causes skipping of exon 2, resulting in the loss of the translation start codon of the BRCA1 protein (PMID: 24667779). This variant has been reported in an individual affected with breast cancer (PMID: 22034289). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 22, 2022
The c.80+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the BRCA1 gene. This alteration has been identified in several breast/ovarian cohorts from China, Europe, Africa, and North America (Fackenthal JD et al. Int. J. Cancer, 2012 Sep;131:1114-23; Shi T et al. Int. J. Cancer, 2017 05;140:2051-2059; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, a mini-gene splicing assay indicated that the c.80+1G>A mutant construct resulted in an abnormal transcript lacking exon 2 (Steffensen AY et al. Eur. J. Hum. Genet., 2014 Dec;22:1362-8). Of note, this alteration is also designated IVS2+1G>A in the published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as disease-causing mutation. -